Platelets contribute to processes beyond thrombus formation and may play a so far underestimated role as an immune cell in various circumstances. This review outlines immune functions of platelets in host defense, but also how they may contribute to mechanisms of infectious diseases. A particular emphasis is placed on the interaction of platelets with other immune cells. Furthermore, this article outlines the features of atherosclerosis as an inflammatory vascular disease highlighting the role of platelet crosstalk with cellular and soluble factors involved in atheroprogression. Understanding, how platelets influence these processes of vascular remodeling will shed light on their role for tissue homeostasis beyond intravascular thrombosis. Finally, translational implications of platelet-mediated inflammation in atherosclerosis are discussed.

Rationale:: Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in inflammatory and autoimmune pathologies is thus far poorly defined. Objective:: We addressed the role of platelets in mediating CNS inflammation in EAE. Methods and Results:: We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but not in the CNS from control nondiseased mice. Platelet depletion at the effector-inflammatory phase of EAE in mice resulted in significantly ameliorated disease development and progression. EAE suppression on platelet depletion was associated with reduced recruitment of leukocytes to the inflamed CNS, as assessed by intravital microscopy, and with a blunted inflammatory response. The platelet-specific receptor glycoprotein Ibα (GPIbα) promotes both platelet adhesion and inflammatory actions of platelets and targeting of GPIbα attenuated EAE in mice. Moreover, targeting another platelet adhesion receptor, glycoprotein IIb/IIIa (GPIIb/IIIa), also reduced EAE severity in mice. Conclusions:: Platelets contribute to the pathogenesis of EAE by promoting CNS inflammation. Targeting platelets may therefore represent an important new therapeutic approach for MS treatment.

During the prolonged course of atherosclerotic disease,platelets are of central importance as they contribute to the initiation of the disease, to its progression and acute exacerbation but also provide potential regenerative mechanisms. Platelets secrete chemokines and cytokines that mediate vascular inflammation and are in turn activated by substances released from cells of the vascular wall.These interactions represent positive and negative feedback loops, which in case of dysregulation may lead to development and progression of disease. Furthermore, platelet adhesion to the endothelium is critical for the initiation of atherosclerotic lesion formation in vivo. Even prior to endothelial denudation, platelet adhesion governed by disturbed flow at predilection sites for atherosclerosis induces recruitment of proathe- rosclerotic cells and release of proinflammatory mediators from all involved cell types.Finally,the pathogenetic role of platelets for late atheroclerotic events including plaque rupture, microembolism or spasms within the microcirculation is well established. However, increasing evidence indicates that platelets mediate on the other hand potential regenerative mechanisms. Platelets recruit circulating progenitor cells to sites of vascular injury. Furthermore, they influence their biological activity and maturation. Therefore,platelets contribute at all stages of vascular disease by interfering with highly dynamic processes. Understanding interactions of platelets with other circulating cells and the vascular wall is a prerequisite to understand cardiovascular disease and to identify potential therapeutic targets.

Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed various intersection points between thrombosis, hemostasis, and inflammation, which are addressed and discussed in this review in detail. One such example is the intrinsic coagulation cascade that is initiated after platelet activation thereby further propagating and re-enforcing wound healing or thrombus formation but also contributing to the pathophysiology of severe diseases. FXII of the intrinsic pathway connects platelet activation with the coagulation cascade during immune reactions. It can activate the contact system thereby either creating an inflammatory state or accelerating inflammation. Recent insights into platelet biology could show that platelets are equipped with complement receptors. Platelets are important for tissue remodeling after injury has been inflicted to the endothelial barrier and to the subendothelial tissue. Thus, platelets are increasingly recognized as more than just cells relevant for bleeding arrest. Future insights into platelet biology are to be expected. This research will potentially offer novel opportunities for therapeutic intervention in diseases featuring platelet abundance.

Beyond platelets function in hemostasis, there is emerging evidence to suggest that platelets contribute crucially to inflammation and immune responses. Therefore, considering the detrimental role of inflammatory conditions in severe neurological disorders such as multiple sclerosis or stroke, this review outlines platelets involvement in neuroinflammation. For this, distinct mechanisms of platelet-mediated thrombosis and inflammation are portrayed, focusing on the interaction of platelet receptors with other immune cells as well as brain endothelial cells. Furthermore, we draw attention to the intimate interplay between platelets and the complement system as well as between platelets and plasmatic coagulation factors in the course of neuroinflammation. Following the thorough exposition of preclinical approaches which aim at ameliorating disease severity after inducing experimental autoimmune encephalomyelitis (a counterpart of multiple sclerosis in mice) or brain ischemia-reperfusion injury, the clinical relevance of platelet-mediated neuroinflammation is addressed. Thus, current as well as future propitious translational and clinical strategies for the treatment of neuro-inflammatory diseases by affecting platelet function are illustrated, emphasizing that targeting platelet-mediated neuroinflammation could become an efficient adjunct therapy to mitigate disease severity of multiple sclerosis or stroke associated brain injury.